Shift work, insufficient sleep and other disrupters of circadian activity increase the risk of metabolic syndrome, characterized by obesity, insulin resistance, dyslipidemia, hypertension, and cardiovascular morbidity. The next cycle of Project #3 will investigate interactions of the brain and peripheral organs in a feeding entrainment model in mice that mimic metabolic disorders resulting from circadian disruption in humans. Mice restricted to 5 hours feeding during the light cycle (L-Fed) develop hypothalamic leptin insensitivity and elevation of resistin levels in 1 week, followed by hepatic steatosis, insulin resistance and obesity. Hepatic CREB coactivator (Crtc2) is increased and Akt activation is blunted in L-Fed mice. We hypothesize that the signaling of leptin and resistin in the brain and liver are crucial for the pathogenesis of steatosis, insulin resistance and obesity in L-Fed mice. Aim 1 will determine how enhanced leptin sensitivity in the hypothalamus resulting from Tyr985 knock-in mutation in the leptin receptor or Socs3 deletion in AGRP and POMC neurons affects energy homeostasis, and glucose and lipid metabolism during feeding entrainment. Aim 2 will determine how leptin interacts with Crtc2 and Akt2 in the liver to regulate glucose and lipid metabolism during feeding entrainment. Aim 3 will determine whether resistin knockout mice are protected against insulin resistance during feeding entrainment, and whether Socs3 mediates resistin's ability to induce insulin resistance. The proposed studies will address critical mechanisms underiying the development of obesity and metabolic dysregulation in mice restricted to feeding during the day. The project will benefit from collaborations with other P01 investigators, and has the potential to provide novel pathophysiological mechanisms and therapies for obesity, diabetes and dyslipidemia associated with disruption of circadian rhythms. RELEVANCE (See instructions): Shift work and other activities that disrupt circadian rhythms increase the risk of obesity, diabetes and heart disease. This project will evaluate the metabolic effects of fat-derived hormones in a mouse model that resembles circadian disruption in humans. We will determine how disruption of the timing of feeding affects the actions of leptin and resistin, and how these fat hormones act in the brain and peripheral organs to cause fatty liver, insulin resistance and obesity.